Drug Coated Balloon Catheter

ABSTRACT

The present invention relates to balloon catheters for treating a luminal system of a patient. Specifically, the invention relates to catheters having a flexible membrane positioned at a distal portion of the catheter, the flexible membrane retained in a substantially unexposed conformation prior to deployment. Preferably the flexible membrane is capable of delivering a therapeutic agent to a localized environment when deployed to an exposed conformation.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation-in-part of U.S. patent applicationSer. No. 12/171,134, filed Jul. 10, 2008, which claims priority to U.S.Provisional Application Ser. No. 60/949,736, filed Jul. 13, 2007, eachof which is hereby incorporated by reference.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates to balloon catheters for treating theluminal systems of a patient. Specifically, the invention relates tocatheters having a flexible membrane positioned at a distal portion ofthe catheter where the flexible membrane is retained in a substantiallyunexposed conformation prior to deployment. Preferably the flexiblemembrane is capable of delivering a therapeutic agent to a localizedenvironment when deployed to an exposed conformation.

2. Description of the Related Art

Heart and vascular disease are major problems in the United States andthroughout the world. Conditions such as atherosclerosis result in bloodvessels becoming blocked or narrowed. If this blockage or narrowing of avessel occurs in the coronary arteries supporting the heart, whichdeliver oxygenated blood, this will have significant consequences, sincethe heart muscle must be well oxygenated in order to maintain its bloodpumping action.

Occluded, stenotic, or narrowed blood vessels may be treated with anumber of relatively non-invasive medical procedures includingpercutaneous transluminal angioplasty (PTA), percutaneous transluminalcoronary angioplasty (PTCA), and atherectomy. Such angioplastytechniques typically involve the use of a balloon catheter. Commonly,the balloon catheter is initially advanced over a guidewire so that theballoon is positioned adjacent a stenotic lesion. Once in place, theballoon is then inflated, and the restriction of the vessel is opened.

Typically, balloon catheters are structured such that they have aballoon fastened at least at one end around the exterior of a hollowcatheter shaft. The hollow interior of the balloon is in a fluid flowrelation with the hollow interior of the shaft. Fluid under pressure canthereby be supplied to the interior of the balloon through the shaft inorder to expand the balloon against an obstruction.

Presently catheter balloon materials may be classified as compliant,semi-compliant, or non-compliant balloons. Compliance can be defined asthe increase in the balloon diameter above nominal balloon pressure.Generally, non-compliant balloons have less increase in diameter, thansemi-compliant balloons, which in turn have less increase in diameterthan compliant balloons.

Compliant balloons expand and stretch with increasing pressure withinthe balloon, and are made from such materials as silicone, thermoplasticelastomers (TPEs), and polyethylene or polyolefin copolymers.Non-compliant balloons, made from such materials as polyethyleneterephthalate (PET) or polyamides, remain substantially at apre-selected diameter as the internal balloon pressure increases beyondthat required to fully inflate the balloon.

Compliant balloon materials provide a degree of softness to the balloonwhich aids its passage through, and expansion within, e.g., bloodvessels. Known compliant balloon materials also can display goodabrasion and puncture resistance at thicknesses typically used formedical device balloons. In light of the foregoing, it is one object ofthe present invention to provide a balloon catheter that employs acompliant balloon.

It is an object of the present invention to provide a device that isuseful for recovering a balloon predictably and compactly upon deflationto facilitate in vivo movement of the balloon catheter.

In addition to the above-described uses of balloon catheters in PTA,PTCA, and atherectomy, some balloon catheters are made to delivertherapeutic drugs or agents. For example, some balloon catheters delivera systemic bolus of liquid that includes a drug to a targeted tissuelocation using an open catheter lumen or channel located at some lengthalong the catheter shaft. Alternatively, the drug can be delivered bycoating it on the exterior of the balloon. Unfortunately, when suchdelivery methods are used to deliver a controlled volume of medicationto a desired tissue location, medication may be lost to systemiccirculation either because of an inability of the drug to quicklypenetrate local tissue, or because the drug coating has been washedaway.

In general, liquid formulations containing a drug or agent that aredelivered to a targeted tissue location by liquid bolus may notpenetrate the tissue sufficiently at the targeted tissue location toresult in a significant therapeutic effect, and may be washed away bybody fluids. Similarly, drug coated on the surface of a balloon can bewashed away due to contact with a circulatory environment, as thecirculatory environment matches the environment the drug is designed totarget. Such systemic dilution substantially diminishes theeffectiveness of the drugs or agents, and increases the likelihood of agreater systemic effect caused by the quantity of drug or agent washedinto the bloodstream.

In light of the foregoing, there is a need for an improved ballooncatheter capable of delivering therapeutics in a safe and effectivemanner to targeted tissues within the body. The present inventionincludes embodiments directed toward solutions that address this unmetneed.

SUMMARY OF THE INVENTION

The purpose and advantages of the present invention will be set forth inand apparent from the description that follows, as well as will belearned by practice of the invention. Additional advantages of theinvention will be realized and attained by the methods and systemsparticularly pointed out in the written description and claims hereof,as well as from the appended drawings.

To achieve these and other advantages and in accordance with the purposeof the invention, as embodied herein and broadly described, theinvention includes a balloon catheter with an inner shaft member havinga proximal end portion, a distal end portion, and a length therebetween.The balloon catheter also includes an outer shaft member that is movablerelative to the inner shaft member and has a proximal end portion, adistal end portion, and a length therebetween. The balloon catheterfurther includes an annular flow passage disposed between the inner andouter shaft members and a flexible membrane extending between the distalend portion of the inner shaft member and the distal end portion of theouter shaft member. This flexible membrane includes both an innersurface and an outer surface and the inner surface is configured suchthat it is in fluid communication with the annular flow passage. Theinner and outer shaft members of the balloon catheter define a chamberconfigured to receive the flexible membrane therein. In furtheraccordance with the invention, the flexible membrane can include atherapeutic agent disposed thereon.

In accordance with a further aspect of the invention, the sealedenvironment of the annular flow passage can be maintained duringmovement of the outer shaft relative to the inner shaft of the ballooncatheter by the inclusion of a bellows component disposed at theproximal end portion of the outer shaft member, or by the inclusion of adynamic seal disposed between the inner shaft member and the outer shaftmember.

In accordance with another aspect of the invention, the flexiblemembrane of the balloon catheter includes at least one driver segmentand a delivery segment, where the driver segment defines at least aportion of a chamber configured to receive the delivery segment. Inaddition, the driver segment can be constructed of a material havingdifferent compliance than that of the delivery segment. Such driversegments can be constructed of materials more or less compliant than thematerial used to construct the delivery segment. Additionally, thedriver segment or segments function to enfold the delivery segment.

In accordance with a further aspect of the invention, the ballooncatheter, when in a pre-deployed condition, includes a flexible membranehaving spiral formations. Such spiral formations of the flexiblemembrane can be the result of rotational movement of the outer shaftmember relative to the inner shaft member.

The invention also includes a method of treating a luminal system of apatient. The method includes providing a balloon catheter as describedherein, positioning the balloon catheter at a desired deployment site,introducing inflation fluid into the annular flow passage, and movingthe outer shaft member relative to the inner shaft member to deploy theflexible membrane into an expanded configuration in order to treat theluminal system of the patient. In accordance with a further aspect ofthe invention, the method of treating a luminal system of a patientincludes initial deployment of the flexible membrane to at leastpartially occlude the luminal system of the patient prior to fullexpansion of the flexible membrane. In yet another aspect of theinvention, the method of treating a luminal system of a patient wherethe flexible membrane includes a therapeutic agent disposed thereon isprovided.

In accordance with a further aspect of the invention, the method oftreating a luminal system of a patient includes collapsing the flexiblemembrane after deployment and treatment of the luminal system of thepatient. Such collapse of the flexible membrane can be achieved bywithdrawing inflation fluid from the annular flow passage or by movementof the outer shaft member axially or rotatably relative to the innershaft member.

In accordance with a further aspect of the invention, the method oftreating a luminal system of a patient includes repositioning theflexible membrane upon collapse into a chamber configured to receivethat membrane, where the chamber is defined by the outer shaft memberand the inner shaft member.

The accompanying drawings, which are incorporated in and constitute partof this specification, are included to illustrate and provide a furtherunderstanding of the methods and systems of the invention. Together withthe description, the drawings serve to explain the principles of theinvention.

BRIEF DESCRIPTION OF THE DRAWINGS

These drawings illustrate certain aspects of some of the embodiments ofthe present invention, and are not intended to be limiting.

FIG. 1 is a schematic side view of a first representative embodiment ofa balloon catheter in accordance with the present invention with adetail cross-sectional view of a flexible membrane at a distal endthereof, and FIG. 1A is an detail view of a dynamic seal near theproximal end of the catheter in accordance with one embodiment of thepresent invention.

FIG. 1B is a schematic side view of another representative embodiment ofa balloon catheter of the present invention, including a bellowscomponent disposed on the outer shaft member.

FIG. 1C is a schematic side view of another representative embodiment ofa balloon catheter of the present invention, including a dynamic sealintegrated into a hub disposed at the proximal end of the catheter.

FIG. 2 is a cross sectional view of the distal end of a balloon catheterin accordance with the embodiment of FIG. 1 wherein the flexiblemembrane is partially deployed.

FIG. 3 is a cross sectional view of the distal end of a balloon catheterin accordance with the embodiment of FIG. 1 wherein the flexiblemembrane is further deployed.

FIG. 4 is a cross sectional view of the distal end of a balloon catheterin accordance with the embodiment of FIG. 1 wherein the flexiblemembrane is fully deployed.

FIG. 5 is a cross sectional view of the distal end of a balloon catheterin accordance with an alternative embodiment of the present inventionwherein the flexible membrane is partially deployed.

FIG. 6 is a cross sectional view of the distal end of a balloon catheterin accordance with the embodiment of FIG. 5 wherein the flexiblemembrane is further deployed.

FIG. 7 is a cross sectional view of the distal end of a balloon catheterin accordance with the embodiment of FIG. 5 wherein the flexiblemembrane is fully deployed.

FIG. 8 is a cross sectional view of the distal end of a balloon catheterprior to deployment of the flexible membrane in accordance with anotherembodiment of the present invention.

FIG. 9 is a cross sectional view of the distal end of a balloon catheterin accordance with the embodiment of FIG. 8 wherein the flexiblemembrane is partially deployed.

FIG. 10 is a cross sectional view of the distal end of a ballooncatheter in accordance with the embodiment of FIG. 8 wherein theflexible membrane is fully deployed.

FIG. 11 is a cross sectional view of the distal end of a ballooncatheter prior to deployment of the flexible membrane in accordance withanother embodiment of the present invention wherein the flexiblemembrane is attached in an advantageous conformation.

FIG. 12 is a cross sectional view of the distal end of a ballooncatheter of FIG. 11 after deployment of the flexible membrane whereinthe flexible membrane is attached in an advantageous conformation.

FIG. 13A is a cross sectional view of the distal end of a ballooncatheter in accordance with another embodiment of the present inventionprior to deployment of the flexible membrane.

FIG. 13B is a cross sectional view of the distal end of a ballooncatheter in accordance with the embodiment of FIG. 13A in the process ofdeployment of the flexible membrane.

FIG. 13C is a cross sectional view of the distal end of a ballooncatheter in accordance with the embodiment of FIG. 13A after deploymentof the flexible membrane.

FIG. 14 is a schematic side view of another representative embodiment ofa balloon catheter of the present invention wherein the flexiblemembrane is arranged in a twisted conformation prior to deployment.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

Reference will now be made in detail to the present preferredembodiments of the invention, examples of which are illustrated in theaccompanying drawings. The methods and corresponding steps of theinvention will be described in conjunction with the detailed descriptionof the system.

The devices and methods presented herein can be used for treating theluminal systems of a patient. The present invention is particularlysuited for treatment of the cardiovascular system of a patient, such asdelivery of therapeutic agents to specific locations within thepatient's circulatory system.

In accordance with the present invention a balloon catheter is providedwith an inner shaft member having a proximal end portion, a distal endportion, and a length therebetween. The balloon catheter also includesan outer shaft member that is movable relative to the inner shaftmember, and has a proximal end portion, a distal end portion, and alength therebetween. The balloon catheter further includes an annularflow passage disposed between the inner and outer shaft members and aflexible membrane extending between the distal end portion of the innershaft member and the distal end portion of the outer shaft member. Thisflexible membrane includes both an inner surface and an outer surfacewith the inner surface configured such that it is in fluid communicationwith the annular flow passage.

For purpose of explanation and illustration, and not limitation,exemplary embodiments of a balloon catheter for use in a cardiovascularsystem and other coronary indications in accordance with the inventionare shown in FIGS. 1A-4. Additional features, aspects, and embodimentsof a balloon catheter in accordance with the invention are provided inFIGS. 5-14, as will be described. The method of use of therepresentative embodiments will be described in conjunction with thedevice.

For purposes of illustration and not limitation, as embodied herein andas depicted in FIGS. 1A-1C, the balloon catheter 100 has an inner shaftmember 10 having a proximal end portion 12, a distal end portion 14, anda length therebetween. The balloon catheter 100 also includes an outershaft member 20 that is movable relative to the inner shaft member 10,and has a proximal end portion 22, a distal end portion 24, and a lengththerebetween.

The inner and outer shaft members 10, 20 of the balloon catheter 100 canbe constructed of any suitable material including but not limited topolymer materials such as nylon, urethane, polyurethane, PEEK, PTFE,PVDF, Kyner, PE, HDPE or polyethylene of various suitable densities. Asa further exemplary alternative, the inner and outer shaft members 10,20 can be constructed of a composite comprising a fabrication of severaldifferent materials, such as a co-extrusion of different polymers, or afiber-reinforced composite material such as fiber reinforced resinmaterials or braided materials. The inner and outer shaft members 10, 20can also be constructed of alloy materials, and metallic materials suchas stainless steel hypodermic tubing which is available from MicroGroup®Inc., Medway, Md. among other vendors.

It is further contemplated that the inner and outer shaft members 10, 20can be constructed of any bio-compatible material. As such, the innerand outer shaft members 10, 20 of the balloon catheter 100 can beconstructed from the above-identified polymers, combinations or blendsof these polymers, whether alone or in combination with other materials,or other bioabsorbable materials.

The inner and outer shaft members 10, 20 can be manufactured using avariety of known techniques such as but not limited to: extrusion,injection molding, air-blowing, stretching, deep drawing,polymerization, cross-linking, dipping from solution, powderdepositioning, sintering, electro-spinning, melt spinning, deformationunder temperature, stretch blowing, chemical grafting any combination ofthe above with reinforcement element like metal braids, coils, glassfibers, carbon fibers and other kind of organic or inorganic fibers,liquid crystals, as well as classical machining technologies likemilling, drilling, grinding, etc. In the event that metallic elementssuch as hypotubes, are to be incorporated, various metallicmanufacturing techniques can be used, such as but not limited to,machining, tube drawing processes, drilling, milling EDM, otherdeformation methods, plating sputtering, electrografting, sintering, anddepositioning e-polishing, among others. Additionally, the inner andouter shaft members 10, 20 can be constructed from polypropylene orurethane by an extrusion process using an extruder such as thatavailable any of a number of known suppliers, such as Medical ExtrusionTechnologies, Inc. Murieta, Calif. U.S. Biosynthetic polymer materialscan be constructed in a bioreactor according to the process disclosed inU.S. Pat. No. 6,495,152, the entirety of which is hereby incorporated byreference. The materials can be post processed in a number of waysincluding, for example and not by way of limitation, extrusion, molding,such as by injection or dipping, textile processing such as weaving orbraiding, and forming. Forming processes that can be suitable arerolling and welding sheets of material or vacuum forming into tubularshapes, to name only a few examples.

The inner and outer shaft members 10, 20 can be further coated with anyof a variety of materials and techniques to enhance performance ifdesired, including a number suitable coatings and coating techniquessubject to patent matters owned by Abbott Laboratories such as U.S. Pat.No. 6,541,116, U.S. Pat. No. 6,287,285, and U.S. Patent Publication No.2002/0009535, the entireties of which are hereby incorporated byreference. For example, possible coating materials include lubriciousmaterials such as Teflon® available from DuPont De Nemours, Wilmington,Del., U.S., and hydrophobic materials such as silicone lubricantdispersion PN 4097, available from Applied Silicone Corp., Ventura,Calif., U.S., or hydrophilic materials such as hydrogel available fromHydromer, Branchburg, N.J., U.S., or lubricious coatings such as thoseavailable from Hydro-Silk of Merritt Island, Fla., U.S.

The inner and outer shaft members 10, 20 can have any suitablecross-sectional shape, including elliptical, polygon, or prismatic,although a circular cross-section generally is preferred. For a coronaryballoon, the cross-sectional dimension generally is between about 0.01millimeters to about 1.50 millimeters, preferably between about 0.10millimeters and about 1.20 millimeters, most preferably between about0.25 millimeters and about 1.00 millimeters. It will be appreciated thata balloon used for non-coronary medical applications would havedifferent dimensions, and that this invention can be modified for use inthose applications. Furthermore, in the case of a balloon catheter 100with a “rapid exchange” (RX) guidewire design, the balloon catheter 100can have an overall length between about 110 centimeters and 400centimeters, preferably between about 120 centimeters and about 350centimeters, more preferably the balloon catheter 100 has a lengthbetween about 120 centimeters and about 310 centimeters, and mostpreferably about 135 centimeters. In the case of a balloon catheter 100with an “over the wire” (OTW) guidewire design, the balloon catheter 100can have an overall length between about 110 centimeters and 400centimeters, preferably between about 120 centimeters and about 350centimeters, more preferably the balloon catheter 100 has a lengthbetween about 120 centimeters and about 310 centimeters, and mostpreferably about 300 centimeters.

In general, the inner shaft member 10 of the instant invention willpreferably include an inner lumen 15. In some embodiments, the innerlumen 15 functions as a guidewire lumen. Accordingly, the ballooncatheter 100 can be advanced over the guidewire 110 to the desiredlocation. The guidewire lumen 15 can extend along essentially the entirelength of the inner shaft member 10 so that the balloon catheter 100resembles traditional “over-the-wire” catheters, as are well known inthe art. Alternatively, the guidewire lumen 15 can extend along only aportion of the inner shaft member 10 so that the balloon catheter 100resembles “single-operator-exchange” or “rapid-exchange” catheters, asare also well known in the art. Furthermore, “fixed wire” designs, asare well known in the art, may be used in connection with the instantinvention as well.

Referring now to FIGS. 2-4, there is shown a partial cross-sectionalside view of the distal end portion of the balloon catheter 100. Asshown in FIGS. 2-4, a flexible tip 40 can extend from the distal endportion 14 of the inner shaft member 10. A variety of distal tipconfigurations are known and used in the art, each generally capable ofperforming particular functions. In addition, the tip 40 can include ablunt tip or a tip having a pre-formed curve which functions as anatraumatic tip thereby allowing the balloon catheter 100 to be insertedwithin a patient's vasculature. Such a pre-formed curve ensures that theblunt tip does not pierce the vessel/artery or organ through which theballoon catheter 100 is being advanced. This and other tip designs arewell known in the art.

In accordance with another aspect of the invention, the outer shaftmember 20 and the inner shaft member 10 define an annular flow passage25. In certain embodiments, the proximal end portion of the annular flowpassage 25 will be either sealably connected directly to an inflationhub unit 30 as shown in FIGS. 1B and 1C, or indirectly to an inflationhub unit 30 via an inflation lumen 14 and dynamic seal 32 as shown inFIGS. 1 and 1A. The sealed environment of the annular flow passage 25can be maintained during inflation of the flexible membrane and movementof the outer shaft member 20 relative to the inner shaft member 10 dueto the presence of a dynamic seal 32, 36 disposed between the outershaft member 20 and the inner shaft member 10, such as shown in FIGS. 1Aand 1C. In certain embodiments this dynamic seal 32 can be locatedproximal to the inflation hub unit 30, while in other embodiments it canbe located distal to the inflation hub unit 30. In accordance withalternative embodiments of the instant invention, the sealed environmentof the annular flow passage 25 will be maintained by the presence of abellows component 34 at the proximal end portion 22 of the outer shaftmember 20 as shown in FIG. 1B.

As used herein, the term “flexible membrane,” refers to that portion ofthe balloon catheter 100 capable of undergoing deformation upon theintroduction of fluid into the annular flow passage 25. The flexiblemembrane, referenced in the embodiments herein for purpose ofillustration by reference number 50, can be constructed in a manner suchthat it exhibits noncompliant characteristics, compliantcharacteristics, or any combination thereof. The flexible membrane 50can be made of any of a variety of known and suitable materials, asselected for the intended purpose of the balloon catheter 100.Furthermore, if desired, the flexible membrane 50 can be formed ofgenerally inflexible segments joined in a manner to facilitate agenerally flexible arrangement that can be deployed as described indetail below. The flexible membrane 50 generally includes a proximal endportion, an intermediate portion, and a distal end portion. The proximalend portion and the distal end portion function as mounting portions toenable the flexible membrane 50 to be mounted to the inner or outersurface of the outer shaft member 20 and the outer surface of the innershaft member 10 to define the annular flow passage 25 of the ballooncatheter 100. With the proximal portion and the distal portion mountedto the inner and outer shaft members 10, 20, the annular flow passage 25is in sealed fluid communication with the flexible membrane 50.

In accordance with particular embodiments of the present invention, theflexible membrane 50 is mounted to the inner and outer shaft members 10,20 in a configuration that facilitates retraction of the flexiblemembrane 50 and/or withdrawal of the balloon catheter 100. For example,in a preferred embodiment, the outer surface of the flexible membrane 50can be mounted to the inner surface of the outer shaft member 20 and theouter surface of the inner shaft member 10 to introduce shoulders asillustrated in FIGS. 11 and 12. Alternative configurations suitable fordeployment of the flexible membrane 50 also can be used.

Mounting of the flexible membrane 50 to the inner and outer shaftmembers 10, 20 can be achieved through use of an adhesive, welded bond(e.g., thermal or chemical weld bond), swaging of metal rings or otherknown attachment methods or combinations thereof. optionally, a band,such as a radiopaque marker band, can be utilized to attach the proximalportion and/or the distal portion of the flexible membrane 50 to theinner or outer shaft members 10, 20 or can be used in combination withthe above processes. Additional radiopaque markers or marker bands canbe secured to the outer surface of the inner or outer shaft members 10,20 at any position along their length, including within the annular flowpassage 25 of the balloon catheter 100.

The marker bands are preferably constructed of materials that facilitateor provide radiopacity. These materials can include, but are not limitedto, platinum, alloys of platinum, gold, tungsten, tantalum, orcombinations thereof, metals, alloys, plastic, polymer, syntheticmaterial, combinations thereof, or other materials that provide anappropriate radiopaque signature. Alternatively, portions of the ballooncatheter 100, including the flexible membrane 50 and/or the inner orouter shaft members 10, 20 can be coated with an appropriate radiopaquematerial, such as, but not limited to, barium sulphate, bismuthsubcarbonate, titanium dioxide, or combinations thereof, to provideradiopacity.

The flexible membrane 50 can be constructed of one or morebio-compatible materials as is known, and if desired, from absorbablebiomaterials. One such material is biosynthetic polyester which,advantageously, is tissue compatible and is constructed of componentmolecules that occur naturally in mammals. The biosynthetic polyesterexhibits desirable characteristics for flexible medical devices. Forinstance, biosynthetic polyesters are very flexible; yet exhibit tensilestrengths that are similar to ultrahigh molecular weight polyethylene.These characteristics provide for a flexible membrane 50 that can betracked through tortuosity easily and has an acceptably high burstpressure. Illustrative biosynthetic polyesters are identified above andinclude 4-hydroxybutyrate and 3-hydroxybutyrate, as well aspoly-L-lactide-co-glycolide, poly-dL-lactide-co-glycolide, polyesteramide, chitosan, PBT, and PEG.

As noted above, the balloon catheter 100 can be at least partiallyloaded with therapeutic agent 60 and such loading will generally occurover some portion of the flexible membrane 50. “Therapeutic agent” asused herein, refers to any compound, mixture of compounds, orcomposition of matter consisting of a compound, which produces atherapeutic or useful result. The therapeutic agent 60 can be a polymer,a marker, such as a radiopaque dye or particles, or can be a drug,including pharmaceutical and therapeutic agents, or an agent includinginorganic or organic drugs without limitation. The agent or drug can bein various forms such as uncharged molecules, components of molecularcomplexes, pharmacologically acceptable salts such as hydrochloride,hydrobromide, sulfate, laurate, palmitate, phosphate, nitrate, borate,acetate, maleate, tartrate, oleate, and salicylate.

An agent or drug that is water insoluble can be used in a form that is awater-soluble derivative thereof to effectively serve as a solute, andon its release from the device, is converted by enzymes, hydrolyzed bybody pH or metabolic processes to a biologically active form.Additionally, the agents or drug formulations can have various knownforms such as solutions, dispersions, pastes, particles, granules,emulsions, suspensions and powders. The drug or agent may or may not bemixed with polymer or a liquid as desired.

In an embodiment of the invention, at least one therapeutic agent can beselected from but not limited to anti-proliferative, anti-inflammmatory,antineoplastic, antiplatelet, anti-coagulant, anti-fibrin,antithrombotic, antimitotic, antibiotic, antiallergic and antioxidantcompounds. Thus, the therapeutic agent can be, again without limitation,a synthetic inorganic or organic compound, a protein, a peptide, apolysaccharides and other sugars, a lipid, DNA and RNA nucleic acidsequences, an antisense oligonucleotide, an antibodies, a receptorligands, an enzyme, an adhesion peptide, a blood clot agent includingstreptokinase and tissue plasminogen activator, an antigen, a hormone, agrowth factor, a ribozyme, a retroviral vector, an anti-proliferativeagent including rapamycin (sirolimus), 40-O-(2-hydroxyethyl)rapamycin(everolimus), 40-O-(3-hydroxypropyl)rapamycin,40-O-(2-hydroxyethyoxy)ethylrapamycin, 40-O-tetrazolylrapamycin(zotarolimus, ABT-578), paclitaxel, docetaxel, methotrexate,azathioprine, vincristine, vinblastine, fluorouracil, doxorubicinhydrochloride, and mitomycin, an antiplatelet compound, ananticoagulant, an antifibrin, an antithrombins including sodium heparin,a low molecular weight heparin, a heparinoid, hirudin, argatroban,forskolin, vapiprost, prostacyclin, a prostacyclin analogue, dextran,D-phe-pro-arg-chloromethylketone (synthetic antithrombin), dipyridamole,glycoprotein IIb/IIIa platelet membrane receptor antagonist antibody,recombinant hirudin, a thrombin inhibitor including Angiomax ä, acalcium channel blocker including nifedipine, colchicine, a fibroblastgrowth factor (FGF) antagonist, fish oil (omega 3-fatty acid), ahistamine antagonist, lovastatin, a monoclonal antibodie, nitroprusside,a phosphodiesterase inhibitor, a prostaglandin inhibitor, suramin, aserotonin blocker, a steroid, a thioprotease inhibitor,triazolopyrimidine, a nitric oxide or nitric oxide donor, a super oxidedismutase, a super oxide dismutase mimetic, estradiol, an anticanceragent, a dietary supplement including vitamins, an anti-inflammatoryagent including aspirin, tacrolimus, dexamethasone and clobetasol, acytostatic substance including angiopeptin, an angiotensin convertingenzyme inhibitor including captopril, cilazapril or lisinopril, anantiallergic agent including permirolast potassium, alpha-interferon,bioactive RGD, and genetically engineered epithelial cells. Othertherapeutic agents which are currently available or that can bedeveloped in the future for use with implantable medical devices canlikewise be used and all are within the scope of this invention.

Examples of such antithrombotics, anticoagulants, antiplatelet agents,and thrombolytics include sodium heparin, low molecular weight heparins,heparinoids, hirudin, argatroban, forskolin, vapriprost, prostacyclinand prostacylin analogues, dextran, D-phe-pro-arg-chloromethylketone(synthetic antithrombin), dipyridamole, glycoprotein IIb/IIIa (plateletmembrane receptor antagonist antibody), recombinant hirudin, andthrombin inhibitors such as Angiomax™, from Biogen, Inc., Cambridge,Mass; and thrombolytic agents, such as urokinase, e.g., Abbokinase™ fromAbbott Laboratories Inc., North Chicago, Ill., recombinant urokinase andprourokinase from Abbott Laboratories Inc., tissue plasminogen activator(Alteplase™ from Genentech, South San Francisco, Calif. and tenecteplase(TNK-tPA).

Examples of such cytostatic or antiproliferative agents includerapamycin and its analogs such as everolimus, ABT-578, i.e.,3S,6R,7E,9R,10R,12R,14S,15E,17E,19E,21S,23S,26R,27R,34aS)-9,10,12,13,14,2-1,22,23,24,25,26,27,32,33,34,34a-Hexadecahydro-9,27-dihydroxy-3-[(1R)-2-[(-1S,3R,4R)-3-methoxy-4-tetrazol-1-yl)cyclohexyl]-1-methylethyl]-10,21-dimethoxy-6,8,12,14,20,26-hexamethyl-23,27-epoxy-3H-pyrido[2,1-c][1,4]oxaazacyclohentriacontine-1,5,11,28,29(4H,6H,31H)-pentone;23,27-Epoxy-3Hpyrido[2,1-c][1,4]oxaazacyclohentria-contine-1,5,11,28,29(4H,6H,31H)-pento-ne,which is disclosed in U.S. Pat. No. 6,015,815, U.S. Pat. No. 6,329,386,U.S. Publication 2003/129215, filed on Sep. 6, 2002, and U.S.Publication 2002/123505, filed Sep. 10, 2001, the disclosures of whichare each incorporated herein by reference thereto, tacrolimus andpimecrolimus, angiopeptin, angiotensin converting enzyme inhibitors suchas captopril, e.g, Capoten® and Capozide® from Bristol-Myers Squibb Co.,Stamford, Conn., cilazapril or lisinopril, e.g., Prinivil™ and Prinzide™from Merck & Co., Inc., Whitehouse Station, N.J.; calcium channelblockers such as nifedipine, amlodipine, cilnidipine, lercanidipine,benidipine, trifluperazine, diltiazem and verapamil, fibroblast growthfactor antagonists, fish oil (omega 3-fatty acid), histamineantagonists, lovastatin, e.g. Mevacor™ from Merck & Co., Inc.,Whitehouse Station, N.J. In addition, topoisomerase inhibitors such asetoposide and topotecan, as well as antiestrogens such as tamoxifen canbe used.

Examples of such anti-inflammatories include colchicine andglucocorticoids such as betamethasone, cortisone, dexamethasone,budesonide, prednisolone, methylprednisolone and hydrocortisone.Non-steroidal anti-inflammatory agents include flurbiprofen, ibuprofen,ketoprofen, fenoprofen, naproxen, diclofenac, diflunisal, acetominophen,indomethacin, sulindac, etodolac, diclofenac, ketorolac, meclofenamicacid, piroxicam and phenylbutazone.

Examples of such antineoplastics include alkylating agents such asaltretamine, bendamucine, carboplatin, carmustine, cisplatin,cyclophosphamide, fotemustine, ifosfamide, lomustine, nimustine,prednimustine, and treosulfin, antimitotics such as vincristine,vinblastine, paclitaxel, e.g., TAXOL® by Bristol-Myers Squibb Co.,Stamford, Conn., docetaxel, e.g., Taxotere™ from Aventis S.A.,Frankfurt, Germany, antimetabolites such as methotrexate,mercaptopurine, pentostatin, trimetrexate, gemcitabine, azathioprine,and fluorouracil, and antibiotics such as doxorubicin hydrochloride,e.g., Adriamycin™ from Pharmacia & Upjohn, Peapack, N.J., and mitomycin,e.g., Mutamycin™ from Bristol-Myers Squibb Co., Stamford, Conn., agentsthat promote endothelial cell recovery such as estradiol.

Other agents and materials could conceivably be delivered into a patientanatomy in accordance with the present invention. For example,angiogenetic factors could be delivered. This includes growth factorssuch as isoforms of vasoendothelial growth factor (VEGF), fibroblastgrowth factor (FGF, e.g. beta-FGF), Del 1, hypoxia inducing factor (HIF1-alpha), monocyte chemoattractant protein (MCP-1), nicotine, plateletderived growth factor (PDGF), insulin-like growth factor (HGF),estrogens, follistatin, proliferin, prostaglandin E1 and E2, tumornecrosis factor (TNF-alpha), interleukin 8 (Il-8), hematopoietic growthfactors, erythropoietin, granulocyte-colony stimulating factors (G-CSF)and platelet-derived endothelial growth factor (PD-ECGF). In someembodiments, angiogenesis promoting factors include, but are notintended to be limited to, peptides, such as PR39, PR11 and angiogenin,small molecules, such as PHD inhibitors, or other agents, such as eNOSenhancers.

While the foregoing therapeutic agents are known for their preventiveand treatment properties, the substances or agents are provided by wayof example and are not meant to be limiting. Further, other therapeuticagents that are currently available or may be developed are equallyapplicable for use with the present invention.

If desired or necessary, the therapeutic agent can include a binder tocarry, load, or allow sustained release of an agent, such as but notlimited to a suitable polymer or similar carrier. The term “polymer” isintended to include a product of a polymerization reaction inclusive ofhomopolymers, copolymers, terpolymers, etc., whether natural orsynthetic, including random, alternating, block, graft, branched,cross-linked, blends, compositions of blends and variations thereof. Thepolymer can be in true solution, saturated, or suspended as particles orsupersaturated in the therapeutic agent. The polymer can bebiocompatible, biosolvable, biostable, or biodegradable.

For purpose of illustration and not limitation, the polymeric materialcan include phosphorylcholine linked macromolecules, such as amacromolecule containing pendant phosphorylcholine groups such aspoly(MPCw:LMAx:HPMAy:TSMAz), where MPC is2-methacryoyloxyethylphosphorylcholine, LMA is lauryl methacrylate, HPMAis hydroxypropyl methacrylate and TSMA is trimethoxysilylpropylmethacrylate, and w, x, y, and z are molar ratios of the monomers usedin the feed. These values are typically 23, 47, 25, and 5, respectively,but they are not necessarily the ratios that exist in the finishedpolymer. The polymer is herein referred to generally as “PC polymer.”

The therapeutic agent can include a liquid. The liquid can be any singlesolvent or a combination of solvents. For purpose of illustration andnot limitation, examples of suitable solvents include water, aliphatichydrocarbons, aromatic hydrocarbons, alcohols, ketones, dimethylsulfoxide, tetrahydrofuran, dihydrofuran, dimethylacetamide, acetates,and combinations thereof. Preferably, the solvent is ethanol. Morepreferably, the solvent is isobutanol. Additionally, in another aspectof the invention, multiple therapeutic agents are dissolved or dispersedin the same solvent. For purpose of illustration and not for limitation,dexamethasone, estradiol, and paclitaxel are dissolved in isobutanol.Alternatively, dexamethasone, estradiol, and paclitaxel are dissolved inethanol. In yet another example, dexamethasone, estradiol, and ABT-578,i.e., the rapamycin analog, 3S,6R,7E,9R,10R,12R,14S,15E,17E,-19E,21S,23-S,26R,27R,34aS)9,10,12,13,14,21,22,23,24,25,26,27,32,33,34,34a-Hexadecahydro-9,27-dihydroxy-3-[(1R)-2-[(1S,3R,4R)-3-methoxy-4-tetrazol-1-yl)cyclohexyl]-1-methylethyl]-10,21-dimethoxy-6,8,12,14,20,26-hexamethyl-2-3,27-epoxy-3H-pyrido[2,1-c][1,4]oxaazacyclohentriacontine-1,5,11,28,29(4H,-6H,31H)-pentone;23,27-Epoxy-3H-pyrido[2,1-c][1,4]oxaazacyclohentriacontin-e-1,5,11,28,29(4H,6H,31H)-pentone,are dissolved together in one solvent. Preferably, the solvent isethanol. More preferably, the solvent is isobutanol.

Additionally, the therapeutic agent includes any of the aforementioneddrugs, agents, polymers, and liquids either alone or in combination.

Such therapeutic agents can be applied to the flexible membrane,preferably to the outer surface of the flexible membrane using any of avariety of known techniques suitable for the intended application, thusallowing the presentation of the therapeutic agent to the externalenvironment upon inflation. For example, a variety of techniques toapply a drug to a surface are discussed in various patent applicationsowned by Abbott Laboratories. The therapeutic agent is employed toinduce a therapeutic effect on the tissue at the targeted location inthe patient. The inclusion of the therapeutic agent creates theopportunity to provide a medical or therapeutic effect for tissue thatmakes contact with the flexible membrane. The therapeutic effect can bevaried by the particular therapeutic agent loaded onto the ballooncatheter. In addition, the therapeutic agent will transfer from theballoon catheter to the targeted tissue location of the patient uponsubstantive contact with the flexible membrane, and will generallyremain at or on the targeted tissue location to penetrate the tissue.

In addition to the therapeutic agent, the balloon catheter may be atleast partially loaded with a salt or sugar compound. During expansionof the flexible membrane the salt or sugar compound can be delivered tothe target tissue prior to, or concurrently with, the therapeutic agent.Upon delivery to the target tissue, the compound will recruit fluid fromthe tissue cells. The recruitment of fluid increases the size of thegaps that exist between cells, thereby creating channels for migrationof the therapeutic agent. By making the path of the therapeutic agenteasier, it will be able to penetrate the target tissue to a greaterdepth. In this way, a greater volume of therapeutic agent can bedelivered in order to provide the intended therapeutic effect.

In accordance with another aspect of the invention, the therapeuticagent will generally be formulated to coat the outer surface of theflexible membrane or be physically positioned in a manner such that anefficacious amount of the therapeutic agent does not wash away withbodily fluid passing by the balloon catheter. Techniques for making sucha formulation are well known in the art and include, for example,overlaying a dissolvable film on the coating that allows for the slowrelease of the agent coated by such a film by including within thecoating components that inhibit transfer of the therapeutic coatinguntil heated or expanded. Alternatively, as described above, the agentcan be incorporated into a hydrogel that inhibits loss of the agent dueto the presence of bodily fluids prior to deployment of the flexiblemembrane.

In accordance with alternative aspects of the invention, the therapeuticagent 60 can be physically positioned in a manner such that anefficacious amount of the therapeutic agent 60 is not lost due to thepresence of bodily fluid contacting the balloon catheter 100. Techniquesfor physically positioning therapeutic agents 60 on the flexiblemembrane 50 are well known in the art. Such techniques include, but arenot limited to, the positioning of the therapeutic agent 60 withinchannels or pores on the flexible membrane 50 such that, when in anunexpanded configuration, the channels are inaccessible to the externalenvironment but upon expansion the channels or pores widen and thetherapeutic agent 60 is exposed to the external environment. Inalternative embodiments of the present invention, the therapeutic agent60 is contained within microcapsules attached to the flexible membrane50 and the therapeutic agent 60 is released from the microcapsules byexpansion of the flexible membrane 50.

In accordance with another aspect of the present invention, further lossof therapeutic agent 60 by the presence of bodily fluids passing by theballoon catheter 100 is inhibited by rolling the flexible membrane 50over itself in a generally axial direction, as illustrated in FIG. 2. Insuch an embodiment, the rolled configuration will isolate the flexiblemembrane 50 from contact with the bloodstream during device delivery bymaintaining the flexible membrane 50 within a chamber defined by theouter shaft member 20 and the inner shaft member 10.

Once the balloon catheter 100 is properly placed within a patient'svasculature, the flexible membrane 50 can be unrolled or otherwisedeployed by the introduction of inflation fluid into the annular flowpassage 25 and retraction of the distal end 24 of the outer shaft member20 in a proximal direction relative to the inner shaft member 10. Suchretraction can be accomplished while maintaining the annular flowpassage 25 by the presence of a dynamic seal 32 between the inner andouter shaft members 10, 20 as illustrated in FIG. 1A, by the presence ofa bellows component 34 disposed along the outer shaft member 20 asillustrated in FIG. 1B, or by the presence of a dynamic seal 36 betweenthe inner shaft member 10 and inflation hub unit 30 located at theproximal end 22 of the outer shaft member 20 as illustrated in FIG. 1C.Upon retraction of the outer shaft member 20, the outer surface of theflexible membrane 50 will become partially exposed to the surroundingenvironment. This partial exposure is illustrated in FIG. 2. Fullretraction of the outer shaft member 20 will fully expose the outersurface of the flexible membrane 50 as illustrated in FIG. 3.

Upon retraction, or concurrent therewith, fluid can be communicatedthrough the annular flow passage 25 to inflate and expand the flexiblemembrane 50 such that the distal surface of the flexible membrane 50comes in contact with the vessel wall. Expansion of the flexiblemembrane 50 in response to the introduction of fluid into the annularflow passage 25 is illustrated in FIG. 4. In certain embodiments, theintroduction of fluid during retraction of the outer shaft member 20will be sufficient to induce occlusion of the target vessel by apartially expanded flexible membrane 50, after which complete expansionand treatment can occur.

In an alternative embodiment, the introduction of fluid into the annularflow passage 25 is sufficient in itself to drive the retraction of theouter shaft member 20 relative to the inner shaft member 10, and willlead to inflation of the flexible membrane 50. Such an embodiment isillustrated in FIGS. 5-7, where the flexible membrane 50 preferentiallyexpands in the unconstrained direction and the expansion will cause theflexible membrane 50 to place a proximal load on the outer shaft member20. As will be appreciated by one of skill in the art, a wide variety ofcombinations of retraction and introduction of fluid into the annularflow passage 25 fall within the scope of the instant invention and willaffect retraction of the outer shaft member 20 and inflation of theflexible membrane 50.

In another embodiment, the balloon catheter 100 has a flexible membrane50 generally contained within the annular flow passage 25 prior todeployment, such that the flexible membrane 50 is deployed distally byunraveling in a distal direction. As illustrated in FIG. 13A, as fluidis introduced through the annular flow passage 25, the flexible membrane50 becomes pressurized and is driven forward within the passage. Thisforward progression results in an unraveling of the flexible membrane 50as illustrated in FIG. 13B. Once the flexible membrane 50 is fullyexposed, as illustrated in FIG. 13C, it will expand against the vesselwall.

In order to prevent loss of the therapeutic agent 60 into the bloodstream after deployment, it can be desirable to retrieve the flexiblemembrane 50 within the annular flow passage 25 defined by the inner andouter shaft members 10, 20. Retrieval can be accomplished by pulling orapplying a tensile load on the outer shaft member 20 as shown in FIG.1C. For example, in one embodiment of the instant invention, suchretrieval is accomplished using the proximal end portion 12 of the innershaft member 10 as a retrieval element. By placing a tensile load on theinner shaft member 10, the distal end 14 of the inner shaft member 10will cause the flexible membrane 50 to roll back into the annular flowpassage 25, where the flexible membrane 50 is protected from the flow ofbodily fluid. Such a process of retrieval is illustrated in FIG. 12.

In an alternative embodiment, if the proximal end portion 12 of theinner shaft member 10 is not accessible, it is possible to provide aretrieval element that is not integral to the inner lumen 15 of theinner shaft member 10. For example, this can be accomplished byattaching an element that is associated with the inner shaft member 10and which can apply a compressive load to the inner shaft member 10 overa portion of length proximal to the point of attachment. Examples ofsuch elements include: sutures, wires, tendons, and rods, all of whichcan be connected at the distal end of the inner shaft member.Application of a tensile load to the element would transmit acompressive load to the inner shaft member 10, which would thereby causethe flexible membrane 50 to retract within the annular flow passage 25.

The retraction of the flexible membrane 50 can be aided by configuringthe proximal and distal ends of the flexible membrane 50 as shown inFIG. 11. When configured in this fashion, when the inner shaft member 10is compressed in order to retrieve the flexible membrane 50, the distalend of the flexible membrane 50 is curved or provided with a shapememory in a way that makes it preferentially retract into the annularflow passage 25 without becoming bunched up or folded in a way thatimpedes retrieval.

In an alternative embodiment, loss of the therapeutic agent 60 by thepresence of bodily fluids passing by the balloon catheter 100 can beinhibited by including a flexible membrane 50 having a segmentedconfiguration. As illustrated in FIG. 8, such embodiments can includewhere the flexible membrane 50 consists of three segments: the proximaldriver 52, the distal driver 54, and the intermediate delivery segment56, however, additional embodiments having fewer or more segments arealso specifically contemplated as within the scope of the instantinvention. In one exemplary embodiment, proximal and distal driversegments 52, 54 are configured such that the intermediate deliverysegment 56 is protected from the surrounding environment, and only theintermediate delivery segment 56 of the flexible membrane is coated withtherapeutic agent 60. In certain embodiments it can be preferable tohave the intermediate delivery segment 56 composed of a more or lessflexible material than the proximal and distal driver segments 52, 54.

When fluid is introduced into the annular fluid passage 25, it causesthe proximal and distal driver segments 52, 54 to expand and forces themaway from each other. This separation can be aided by the axialdisplacement of the inner and outer shaft members 10, 20 as discussedabove, and can be the result of the proximal and distal driver segments52, 54 and intermediate delivery segment 56 having different compliance.Such separation is illustrated in FIG. 9.

As the proximal and distal driver segments 52, 54 separate, they exposethe intermediate delivery segment 56 to the surrounding environment. Theunconstrained intermediate delivery segment 56 is then able to expandtoward the vessel wall. Upon further inflation, the proximal and distaldriver segments 52, 54 and the intermediate delivery segment 56 becomefully expanded, bringing the therapeutically coated surface of theintermediate delivery segment 56 in contact with the vessel wall.

In an additional embodiment, the proximal and/or distal driver segments52, 54 can be designed to preferentially expand to occlude the vessel inone or more locations, thereby preventing bodily fluids from contactingthe intermediate delivery segment 56 prior to full inflation of thatsegment. In one such embodiment the proximal driver 52 can expand first,thereby occluding the proximal end of the vessel and preventing the flowof bodily fluid from contacting the intermediate delivery segment 56during deployment of the device.

In order to prevent loss of the therapeutic agent 60 into the bloodstream after deployment of the segmented flexible membrane 50, it may bedesirable to form the proximal and distal driver segments 52, 54 suchthat they preferentially collapse only after the intermediate deliverysegment 56 has collapsed and such that they return to theirpre-deployment configuration.

In an alternative embodiment, as shown in FIG. 14, loss of thetherapeutic agent 60 due to the presence of bodily fluids contacting theballoon catheter 100 can be inhibited by the introduction of spiralformations 58 along the flexible membrane 50. These spiral formations 58can be introduced by configuring the inner and outer shaft members 10,20 such that they are rotatably movable with respect to each other. Asthe flexible membrane 50 is associated with both the inner and outershaft members 10, 20, the rotation of the shaft members relative to eachother will result in a series of spiral formations 58 in the surface offlexible membrane 50, rendering portions of the flexible membrane 50inaccessible to the external environment and the passing bodily fluids.As such portions are not exposed to the surrounding environment; anytherapeutic agent 60 disposed therein would be protected from the bloodstream. Upon proper positioning of the balloon catheter 100, the innerand outer shaft members 10, 20 can be rotated in the reverse directionto remove the spiral formations 58 and the flexible membrane 50 can beinflated to effect transfer of the therapeutic agent 60 to the locationto be treated.

In accordance with another aspect of the instant invention, loss of thetherapeutic agent 60 into the blood stream after deployment of aflexible membrane 50 that has had its spiral formations 58 removed, itwould be possible to reintroduce the spiral formations 58 upon collapseof the flexible membrane 50 by rotating the inner and outer shaftmembers 10, 12 relative to each other. Such reintroduction wouldeffectively prevent the therapeutic agent 60 disposed between the spiralformations 58 from contacting the blood stream during withdrawal orrepositioning of the balloon catheter 100.

It will be appreciated, in light of the embodiments described above,that the invention describes a balloon catheter that can be used in a“universal” fashion. In particular, depending upon the length offlexible membrane deployed, the balloon catheter can be used to treat avariety of disease lengths or treatment sites. The operator can controlthe length of deployment through relative motion of the catheter shaftmembers such as previously described. Such a system is advantageous notonly as it will allow users to stock a single length, but can alsoreduce the need for the user to swap out devices when a longer orshorter flexible membrane is needed than was initially introduced intothe patient.

In accordance with another aspect of the invention and as previouslydescribed in conjunction with certain aspects of the invention, a methodof treating a luminal system of a patient is provided. The methodincludes providing a balloon catheter as described herein, positioningthe balloon catheter at a desired deployment site, introducing inflationfluid into the annular flow passage and moving the outer shaft memberrelative to the inner shaft member to deploy the flexible membrane intoan expanded configuration in order to treat the luminal system of thepatient. As pointed out above, the balloon catheter can take a number ofdifferent configurations and the methods of the instant inventionenvision the use of any such configurations as within their scope.

In accordance with additional aspects of the methods of the instantinvention, the balloon catheter includes properties that facilitate itscollapse and withdrawal. For example, and not by way of limitation, themethods of the instant invention include the withdrawal of inflationfluid from the annular flow passage and movement of the inner and outershaft members relative to each other to effect the collapse of theflexible membrane. In one such embodiment, the method includes axiallymoving the distal end portion of the outer shaft member beyond thedistal end portion of the inner shaft member such that the flexiblemembrane is rendered taut and less likely to catch on luminal structuresas the balloon catheter is withdrawn from the patient. In an alternativeembodiment, the distal end portion of the inner shaft member is movedaxially relative to the outer shaft member such that the distal endportion of the inner shaft member extends beyond the distal end portionof the outer shaft member and the flexible membrane is also renderedtaut and less likely to catch on luminal structures as the ballooncatheter is withdrawn from the patient. In further embodiments, themethods of the present invention make use of other structures of theballoon catheter described above, such as the chamber configured toreceive the flexible membrane defined by the inner and outer shaftmembers, to facilitate collapse of the flexible membrane and withdrawalof the balloon catheter. Methods of using such structures within thescope of the invention, such as the examples provided herein, would bereadily apparent to one of skill in the art.

COMPARATIVE STUDIES

This study compared the effects of Zotarolimus coated angioplastyballoons and Zotarolimus coated stents on the reduction of formation ofneointima commonly associated with restenosis. Also evaluated was theinfluence of Zotarolimus delivered to one coronary artery from a balloonor stent to neotintimal hyperplasia in a separate coronary arteryimplanted with a bare metal stent. The results of this study indicatethe delivery of beneficial agent directly from an angioplasty balloon isan attractive alternative to a drug eluting stent.

STUDY DESIGN/METHODS A. Animals

Domestic Sus Scrofa male, castrated adolescent pigs weighing between 25to 30 kg were used in these studies. Pigs were acquired from V.B. Zuchtund Mast GmbH, Dorfstraβe 12, 39307 Klein Demsin, Germany. During a tenday (minimum) quarantine period and for four additional days, pigsselected from the animal population were given a corn-based high-fiberfeed and unfiltered tap water was provided ad libitum. Samples of thewater were analyzed for total dissolved solids, harness, specifiedmicrobiological content and selected environmental contaminants. Noknown contaminants were identified which would be expected to interferewith the study. The animals were held in quarantine for a minimum of tendays to ensure the health of each animal before the initiation of thestudy.

B. Interventional Procedure and Surgical Preparation

The pigs were pre-sedated by intramuscular injection of ketamine andxylazine. A venous access was provided. After sedation, the animals wereintubated and maintained in anesthesia with intravenous 3 to 10 mlPropofol (Recofol® 1% (Curamed Pharma GmbH, Germany)). The pigs wereintubated (Endonorm 6.5 F, Rusch GmbH, Germany) and ventilation wasstarted using a mixture of 30 vol. % of pure oxygen, 70 vol % N₂O and1-2 vol % of Isofluran (Isofluran Curamed®, Curamed Pharma GmbH,Germany). After induction of anesthesia, an incision was made in theneck to expose the carotid artery. An arterial sheath was introduced andadvanced into the artery. For the interventional procedure, the animalsreceived 5,000 IU of heparin, 250 mg aspirin intravenously (Aspisol®,Bayer AG, Germany), and intracoronary nitroglycerin.

In each of forty-two pigs, one TriMaxx® stent (P) mounted on a bareangioplasty balloon was implanted in a randomly selected artery, i.e.,left anterior descending coronary artery (LAD) or left circumflexcoronary artery (CX). The remaining coronary vessel was randomlyassigned to receive either: (a) a second TriMaxx® stent on a bareballoon (P), (b) a TriMaxx® stent on a drug-eluting balloon (DEB), or(c) a ZoMaxx® drug eluting stent on a bare balloon (DES). Thus, one setof fourteen pigs received two TriMaxx® stents mounted on bareangioplasty balloons in LAD and CX (P-P), a second set of fourteen pigsreceived one TriMaxx® stent mounted on a bare angioplasty balloon in onecoronary artery and a TriMaxx® stent on a drug eluting balloon in theother artery (P-DEB), and a third set of fourteen pigs received aTriMaxx® stent mounted on a bare angioplasty balloon in one artery and aZoMaxx® drug eluting stent on a bare angioplasty balloon in the othercoronary arty (P-DES).

The placebo control was a TriMaxx® Coronary Stent coated withphosphorylcholine (PC) mounted on a PTCA catheter. The drug elutingstent was a ZoMaxx® Coronary Stent coated with PC and Zotarolimuspremounted on a PTCA catheter and the drug eluting balloon was anangioplasty balloon coated with Zotarolimus premounted with a TriMaxx®Coronary Stent.

The coating solution was 0.7 ml ethanol+150 ul Ultravist 370+4.15 mlacetone; thereof 3 ml+135 mg Zotarolimus=45 mg Zotarolimus/mlZotarolimus. Ethanol content of the solution: 14%. The balloons werecoated two times to achieve 13 μl (3.0-17 mm) or 15 μl (3.5-17 mm) byeither an automatically adjustable 50 μl or a conventional 25 μlHamilton syringe. Total consumption/coating step=47×13 μl+59×15μl+losses=1.5 ml+losses. The drying time between coatings was≧3 hrs.

TABLE I Summary of Coating μg/mm² μg/mm balloon balloon Samples n μgZotarolimus surface length % of dose Unused coated balloons with 5 1 200± 46 6.4 ± 0.2 71 ± 3 100 stents 3.5-17 mm Unused coated balloons with 41073 ± 56 6.7 ± 0.3 63 ± 3 100 stents 3.0-17 mm Coated balloons afteruse 15   131 ± 60  7.7 ± 3.5 14.1 ± 11.5 Bare balloons with premounted 4not detectable ZoMaxx stents after use Bare balloons with bare stents 3not detectable after use

The Zotarolimus content of balloons with stents and balloon after stentimplantation was calculated and summarized at Table II.

TABLE II Zotarolimus Content of Balloons With Stents And Balloons AfterImplantation Sample/ Peak area Conc. ABT ABT-578 Animal no*** Peak areaABT Oxepane Total area μg/ml μg % of dose 25 μg/ml   722,842  43,851  766,693 25.00 18/3.5-17 21 439 952  1 620 115   23 060 067  752 1 128  31/3.5-17 22 734 940  1 731 578   24 466 518  798 1 197   38/3.5-17 23266 330  1 718 515   24 984 845  815 1 222   44/3.5-17 22 843 718  1 669004   24 512 722  799 1 199   54/3.5-17 23 859 656  1 772 667   25 632323  836 1 254   Mean ± SD 1 200 ± 46   71/3.0-17 20 545 884  1 629 657  22 175 541  723     1.085 72/3.0-17 10 559 856  1 576 729   12 13 585396 594 88/3.0-17 20 479 530  1 601 586   22 081 116  720     1.08090/3.0-17 18 874 040  1 491 887   20 365 927  664 996 98/3.0-17 21 480138  1 648 244   23 128 382  754     1.131 Mean ± SD 1073 ± 56* 16**/14CX 1 206 986  93 207 1 300 193 42.5   63.8 5.3 19/5 CX 1 186 017 101 0981 287 115 42.0   63.0 5.2 22/43 CX 2 474 350 175 955 2 650 305 86.7 13010.8 25/20 LAD 2 266 034 159 360 2 425 394 79.3 119 9.9 26/7 CX 1 129959  71 187 1 201 146 39.2   58.8 4.9 28/2 LAD 1 817 150 143 416 1 960566 63.9   95.9 8.0 36/32 LAD 4 119 968 300 699 4 420.667 145 217 18.137/34-36 LAD 2 600 973 186 731 2 787 704 91.2 137 11.4 43/3 CX 5 247 028394 311 5 641 339 184 276 23.0 48**/21 CX 2 621 613 195 138 2 816 75192.1 138 11.5 49/17 LAD 3 526 794 261 929 3 788 723 124 186 15.5 51/19LAD 2 996 942 221 358 3 218 300 105 158 13.2 53/10 LAD 2 112 427 145 2452 257 672 73.8 111 9.2 56/24 CX 2 232 040 161 731 2 393 771 78.3 117 9.892**/13 CX 1 828 869 135 997 1 964 866 64.3   96.4 9.0 **) more bloodthan on other balloons 131 ± 60 14.1 ± 11.5 DES/17 no peak DES/23 nopeak DES/27 no peak DES/28 no peak No drug/3LAD no peak No drug/19 CX nopeak No drug/2CX no peak

The Zotarolimus measurements were made according to the followingmethod, the gradient clean up was not performed. Zorbax Eclipse XDB-C8columns sized 4.6×75 mm by 3.5 micrometers, the column temperature of 45degrees centigrade at a flow rate of 1 ml/min, the flow media 51%ammonia acetate buffer ph 4.9; 49% acetone nitrile, injection volume 20micro liters, UV detection 278 nm.

Each stent delivery system was prepared by flushing the guidewire lumenwith heparinized saline solution. Air was aspirated from the balloonlumen using negative pressure, filling lumen with a 50/50 mixture of0.9% normal saline and contrast solution. Stents were then introducedinto the coronary arteries by advancing the stented balloon catheterthrough the guide catheter and over the guidewire to the deployment sitewithin the LAD or CX. The balloon was then inflated at a steady rate toa pressure sufficient to target a stent: artery ratio of 1.2.Confirmation of this stent-artery ratio was made when the angiographicimages were quantitatively assessed. After the target balloon to arteryratio was achieved for 60 seconds, vacuum was applied to the inflationdevice in order to deflate the balloon. The delivery system was removed.

Contrast injections were used to determine device patency and additionalacute system was noted. This process was repeated until all devices weredeployed. All catheters were then removed from the animal and thecarotid artery was ligated. At this time, blood pressure monitoring wasterminated. The incision was closed in layers with suture materials. Theskin was closed with closure materials. The pigs were returned to theircages and allowed to recover from anesthesia. To prevent infection, pigswere given Urocyclin 10% at appropriate dosage levels at least 1 dayprior to implantation and on the day of implantation. Additional doseswere administered as necessary.

After 28 days, the pigs were sacrificed using pentobarbital in deepanesthesia. Hearts were rapidly excised, the coronary system flushedwith 0.9% saline and the arteries fixed by perfusion with 4% bufferedformalin under physiological pressure and overnight immersion. Thetarget segments were then dissected and samples for histology obtained.

C. Data Collection 1. Semi-Quantitative and Quantitative CoronaryAnalysis (QCA)

Coronary imaging was done using a Philips PolyArc fluoroscope connectedto a digitizer using an Apple Macintosch Power PC. A semi-quantitativeevaluation of coronary angiography was performed with the followinggrading: 0=no signs of neointimal hyperplasia (identical with resultimmediately after stent implantation); 1=slight signs of neointimalhyperplasia; 2=moderate signs of neointimal hyperplasia (minimal lumendiameter in-stent identical with vessel reference diameter ); 3=clearsigns of neointimal hyperplasia (minimal lumen diameter in-stentidentical with vessel reference diameter); 4=strong signs of neointimalhyperplasia, about 50% of reference diameter; and 5=distinct signs ofneointimal hyperplasia (vessel nearly or totally occluded). The CAAS IIfor Research System (Pie Medical, the Netherlands) was used forquantitative coronary analysis.

2. Histology

Hearts were rapidly excised, the coronary system flushed with 0.9%saline and the arteries fixed by perfusion with 4% buffered formalinunder physiological pressure and overnight immersion. Stented coronaryarteries were dissected from the formalin-fixed hearts and immersed inmethylmethacrylate (Merck, Darmstadt, Germany). Three representativecross sections per stent were separated from the blocks with a rotationmicrotome (Leica RM 2255), polished, and glued on acrylic plasticslides. Final specimens were stained by HE and Masson-Goldner technique.After digitalizing, histomorphometric measurements were taken with theNIH image program (PC version ‘Scion Image,’ Scion Corporation,Maryland, USA). The evaluated parameters were: luminal area, externalelastic lamina (EEL) diameter, maximal neointimal thickness, EEL area,luminal area, and neointimal area.

Histomorphometric variables of the three cross-sectional planes wereaveraged to obtain a mean value per stent. Continuous variables werecompared by ANOVA analysis using the software package SPSS 13.0 forWindows (SPSS Inc. Chicago, Ill.). Data are presented as the meanvalue±SD.

D. Results

1. Semi-quantitative angiographic coronary analysis

Graph 1 illustrates the comparative results of semi-quantitativeangiographic scoring (narrowed compared to reference diameter score>1)of P (TriMaxx Stent on uncoated balloon), DEB (TriMaxx Stent onZotarolimus coated balloon), and DES (ZoMaxx stent on uncoated balloon).An arbitrary scoring system was used in which 0=still oversized, 1=aboutreference diameter, 2=slightly less than reference diameter,3=significantly less than reference diameter, 4=very narrow but notincluded, 5=occluded. As illustrated below in Graph 1, the angiographicstenosis score reveals a reduction of stenosis by the drug eluting stent(DES) and a further improved reduction of stenosis of the Zotarolimuscoated balloon (DEB) after one month.

Table III below summarizes the individual results of thesemiquantitative angiographic scoring.

TABLE III Individual Results of Semi-Quantitative Angiographic ScoringAnimal number Vessel Vessel  #7 LAD 3-4 CX 0  #8 LAD 2 CX 2  #9 LAD 3-4CX 0-1 #10 died shortly the intervention #11 LAD 3 CX 1 #12 LAD 3 CX 1#13 LAD 2 CX 0 #14 LAD 4 CX occlusion several cm to stent, infarction#15 LAD 4 CX 1 #16 LAD 0-1 CX 1 #17 LAD 3 CX 2 #18 LAD 2-3 CX 1 #19 LAD1 CX 1 #20 LAD 3-4 CX 0 #21 LAD 4 CX 1-2 #22 LAD 1 CX 3 #23 LAD (0)-1  CX 1 #24 LAD 1 CX 1 #25 LAD (0)-1   CX 2 #26 LAD 1 CX 1 #27 LAD 1(-2) CX0 #28 LAD 1 CX 1 #29 LAD 3 CX 0 #30 LAD 4 CX 0 #31 LAD 4 CX (0)-1  #32LAD 1 CX 2 #33 LAD 3(-4) CX 3 #34 LAD 1-2 CX 1 #35 LAD 2 CX (0)-1 #36LAD 1(-2) CX 1 #37 LAD 1(-2) CX (0)-1  #38 died shortly the intervention#39 LAD   1-(2) CX 1 #40 LAD (0)-1  CX 0 #41 LAD 3-4 CX 0-1 #42 LAD 1-2CX 0 #43 LAD 2-3 CX 0-1 #44 LAD 1-2 CX 3 #45 LAD 1-2 CX 0 #46 LAD 3 CX 1#47 LAD 3 CX 1 #48 LAD 1 CX 0-1 #49 LAD 1-2 CX 1-2 #50 LAD 3-4 CX 1Individual results of semi quantitative angiographic scoring. 0 = stilloversized, 1 = about reference diameter, 2 = slightly less referencediameter, 3 significantly less than reference diameter, 4 = very narrowbut not occluded, 5 = occluded. Treatment: Placebo (no drug); DES; DEB.

2. Quantitative Coronary Angiography (QCA)

As illustrated in Tables IV, V, and VI below, QCA reveals a reduction oflate lumen loss by the Zotarolimus coated stent and the Zotarolimuscoated balloon.

TABLE IV Results of QCA P DES DEB p stent implantation RFD [mm] 2.30 ±0.37 2.22 ± 0.39 2.33 ± 0.33 0.688 stent diameter [mm] 2.69 ± 0.31 2.66± 0.28 2.64 ± 0.26 0.826 overstretch [—] 1.18 ± 0.15 1.22 ± 0.17 1.14 ±0.11 0.380 control angiography RFD control [mm] 2.38 ± 0.27 2.31 ± 0.232.31 ± 0.30 0.463 MLD control [mm] 1.44 ± 0.58 1.69 ± 0.45 1.77 ± 0.490.126 late lumen loss [mm] 1.26 ± 0.61 0.96 ± 0.36 0.87 ± 0.47 0.028 RFD= reference diameter at baseline [mm], stent diameter [mm], overstretchratio [—], RFD at control [mm], MLD minimal lumen diameter at control[mm], and late lumen loss [mm]. ANOVA analysis.

TABLE V p-Values of QCA p p p P vs DES P vs DEB DES vs DEB RFD [mm]0.460 0.790 0.421 stent diameter [mm] 0.732 0.575 0.853 overstretch [—]0.432 0.329 0.167 RFD control [mm] 0.323 0.351 0.994 MLD control [mm]0.125 0.122 0.978 late lumen loss [mm] 0.084 0.027 0.550

TABLE VI Results of QCA for LAD only only LAD P DES DEB p stentimplantation RFD [mm] 2.17 ± 0.28 2.01 ± 0.33 2.13 ± 0.19 0.409 stentdiameter [mm] 2.59 ± 0.22 2.58 ± 0.24 2.55 ± 0.24 0.898 overstretch [—]1.21 ± 0.18 1.31 ± 0.21 1.20 ± 0.10 0.395 control angiography RFDcontrol [mm] 2.32 ± 0.24 2.15 ± 0.10 2.16 ± 0.24 0.110 MLD control [mm]1.18 ± 0.50 1.42 ± 0.38 1.42 ± 0.38 0.318 late lumen loss [mm] 1.41 ±0.61 1.15 ± 0.37 1.13 ± 0.37 0.328

TABLE VII Results of QCA for CX only only CX P DES DEB p stentimplantation RFD [mm] 2.44 ± 0.40 2.43 ± 0.35 2.53 ± 0.31 0.829 stentdiameter [mm] 2.78 ± 0.36 2.73 ± 0.33 2.73 ± 0.26 0.886 overstretch [—]1.15 ± 0.11 1.13 ± 0.05 1.08 ± 0.09 0.242 control angiography RFDcontrol [mm] 2.45 ± 0.28 2.46 ± 0.23 2.46 ± 0.29 0.997 MLD control [mm]1.69 ± 0.54 1.96 ± 0.35 2.12 ± 0.29 0.235 late lumen loss [mm] 1.11 ±0.57 0.77 ± 0.22 0.60 ± 0.43 0.153

Tables VIII and IX summarize the individual results of QCA for theanimals in the study.

TABLE VIII Individual QCA Results for animals G59/007-G59/028 ID groupRFD Stent RFD control MLD control overstretch late loss G59007cx P 2.422.71 2.41 1.68 1.12 1.03 G59007lad P 2.31 2.58 2.20 0.82 1.12 1.76G59008cx P 2.14 2.62 2.28 1.50 1.22 1.12 G59008lad DEB 2.13 2.54 1.991.26 1.19 1.28 G59009cx DEB 2.30 2.78 2.21 2.35 1.21 0.43 G59009lad P1.94 2.42 2.16 0.98 1.25 1.44 G59010cx P G59010lad P G59011cx DEB 2.632.89 2.22 2.25 1.10 0.64 G59011lad P 2.19 2.61 1.78 0.85 1.19 1.76G59012cx P 2.80 3.22 2.63 1.88 1.15 1.34 G59012lad P 2.52 2.78 2.67 0.861.10 1.92 G59013cx DEB 2.59 2.76 2.59 1.57 1.07 1.19 G59013lad P 2.242.66 2.39 1.42 1.19 1.24 G59014cx P 2.53 2.93 2.53 0.01 1.16 2.92G59014lad P 1.91 2.58 2.54 0.84 1.35 1.74 G59015cx P 2.40 2.91 2.31 1.841.21 1.07 G59015lad P 1.84 2.91 1.73 0.20 1.58 2.71 G59016cx P 3.07 3.183.11 2.20 1.04 0.98 G59016lad DEB 2.42 2.73 2.29 1.71 1.13 1.02 G59017cxP 1.92 2.72 1.99 1.09 1.42 1.63 G59017lad P 2.57 2.69 2.45 1.59 1.051.10 G59018cx P 2.39 2.52 2.60 1.95 1.05 0.57 G59018lad P 2.23 2.53 2.461.27 1.13 1.26 G59019cx DEB 2.51 2.89 2.65 2.31 1.15 0.58 G59019lad P2.39 2.68 2.21 1.22 1.12 1.46 G59020cx DEB 2.47 2.70 2.35 1.99 1.09 0.71G59020lad P 2.12 2.51 2.16 1.08 1.18 1.43 G59021cx P 2.48 2.48 2.74 1.561.00 0.92 G59021lad P 2.25 2.41 2.51 1.15 1.07 1.26 G59022cx P 2.00 2.382.04 1.08 1.19 1.30 G59022lad P 2.30 2.56 2.48 1.99 1.11 0.57 G59023cx P2.59 2.87 2.42 1.62 1.11 1.25 G59023lad DEB 1.79 2.23 2.13 1.08 1.251.15 G59024cx P 2.76 2.92 2.64 2.68 1.06 0.24 G59024lad P 2.47 2.62 2.452.28 1.06 0.34 G59025cx P 1.85 2.18 2.13 1.38 1.18 0.80 G59025lad DEB2.11 2.35 2.50 1.89 1.11 0.46 G59026cx P 2.72 2.93 2.76 2.18 1.08 0.75G59026lad DEB 2.05 2.82 2.24 1.83 1.38 0.99 G59027cx DEB 2.11 2.16 2.972.36 1.02 −0.20 G59027lad P 2.26 2.48 2.30 1.90 1.10 0.58 G59028cx P2.22 2.54 2.35 1.18 1.14 1.36 G59028lad DES 2.09 2.32 2.24 1.33 1.110.99

TABLE IX Individual QCA Results for animals G59/029-G59/050 MLD ID groupRFD Stent RFD control control overstretch G59029cx DES 2.16 2.53 2.341.71 1.17 G59029lad P 1.50 2.55 2.33 1.18 1.70 G59030cx DEB 3.12 2.902.21 2.02 0.93 G59030lad P 2.57 2.40 2.56 0.69 0.93 G59031cx DES 2.722.82 2.94 2.35 1.04 G59031lad P 2.10 2.73 2.39 0.89 1.30 G59032cx P 2.532.61 2.69 0.83 1.03 G59032lad P 1.97 2.36 2.65 2.05 1.20 G59033cx P 1.852.15 2.05 1.38 1.16 G59033lad DES 1.76 2.40 2.01 0.67 1.36 G59034cx P2.12 2.29 2.18 1.74 1.08 G59034lad DES 2.15 2.45 2.22 1.87 1.14 G59035cxP 2.63 2.84 2.72 2.36 1.08 G59035lad DES 2.43 2.71 2.30 1.35 1.12G59036cx P 1.97 2.44 2.24 2.24 1.24 G59036lad P 2.03 2.23 2.57 1.70 1.10G59037cx P 2.57 3.33 2.84 2.26 1.30 G59037lad P 2.36 2.66 2.36 1.77 1.13G59038cx P G59038lad DEB G59039cx DES 2.00 2.32 2.38 1.45 1.16 G59039ladP 2.18 2.60 2.08 1.12 1.19 G59040cx P 3.06 3.16 2.59 2.09 1.03 G59040ladDES 1.95 2.77 2.09 1.64 1.42 G59041cx DES 3.03 3.33 2.32 2.21 1.10G59041lad P 2.71 3.20 2.34 1.16 1.18 G59042cx P 2.42 2.64 2.55 1.98 1.09G59042lad DEB 2.24 2.80 2.22 1.16 1.25 G59043cx DES 2.25 2.53 2.54 1.631.12 G59043lad P 2.51 2.74 2.45 0.36 1.09 G59044cx P 3.59 3.65 2.72 1.571.02 G59044lad DES 2.27 2.96 2.15 1.58 1.30 G59045cx DES 2.52 2.87 2.372.21 1.14 G59045lad P 1.97 2.39 2.16 1.23 1.21 G59046cx DES 2.33 2.722.32 2.17 1.17 G59046lad P 1.99 2.38 2.42 0.89 1.20 G59047cx P 2.67 3.032.37 1.67 1.13 G59047lad P 1.91 2.38 2.24 1.04 1.25 G59048cx P 2.22 2.762.40 1.97 1.24 G59048lad DES 1.45 2.44 2.07 1.53 1.68 G59049cx P 2.012.80 2.23 1.61 1.39 G59049lad DEB 2.20 2.35 1.73 0.99 1.07 G59050cx P2.60 3.39 2.12 1.72 1.30 G59050lad P 1.82 3.08 1.83 0.64 1.69

3. Histomorphometry

As represented in Tables X, XI, XII, and XIII, histomorphometry revealeda significant reduction of neointimal formation by the Zotarolimuscoated balloon and Zotarolimus coated stent.

TABLE X Results of Histomorphmetry P DES DEB p n 56 14 14 all vesseldiameter [mm] 3.07 ± 0.16 2.94 ± 0.17 3.07 ± 0.16 0.041 lumen diameter[mm] 1.93 ± 0.48 2.15 ± 0.35 2.20 ± 0.37 0.059 max. neoint. thickn. 0.63± 0.37 0.38 ± 0.21 0.49 ± 0.46 0.055 [mm] vessel area [mm²] 7.44 ± 0.797.05 ± 0.49 7.17 ± 1.08 0.196 luminal area [mm²] 3.12 ± 1.25 3.73 ± 0.984.38 ± 1.37 0.003 neointimal area [mm²] 4.32 ± 1.45 3.32 ± 1.11 2.79 ±1.43 0.001 area stenosis [%] 58% ± 17% 47% ± 13% 38% ± 19% 0.001 injuryscore [—] 1.20 ± 0.86 1.25 ± 0.92 1.16 ± 0.43 0.961 inflammation score1.45 ± 0.94 1.65 ± 0.90 0.75 ± 0.86 0.021 [—] Vessel diameter [mm],lumen diameter [mm], maximal neointimal thickness [mm], vessel area[mm²], area stenosis [%], injury score [—], and inflammation score [—].ANOVA analysis.

TABLE XI Comparison of p-Values of Histomorphometry p p p n P vs DES Pvs DEB DES vs DEB vessel diameter [mm] 0.015 0.943 0.054 lumen diameter[mm] 0.109 0.052 0.717 max. neoint. thickn. [mm] 0.018 0.213 0.453vessel area [mm²] 0.083 0.286 0.715 luminal area [mm²] 0.096 0.002 0.161neointimal area [mm²] 0.019 0.001 0.281 area stenosis [%] 0.028 0.0010.186 injury score [—] 0.844 0.885 0.752 inflammation score [—] 0.4820.013 0.012

TABLE XII Results of Histomorphometry for CX only only CX P DES DEB p n28 7 7 vessel diameter [mm] 3.01 ± 0.17 2.85 ± 0.20 3.01 ± 0.17 0.109lumen diameter [mm] 1.93 ± 0.53 2.17 ± 0.17 2.23 ± 0.50 0.426 max.neoint. thickn. 0.53 ± 0.32 0.34 ± 0.11 0.33 ± 0.29 0.254 [mm] vesselarea [mm²] 7.16 ± 0.85 6.74 ± 0.42 6.96 ± 1.14 0.489 luminal area [mm²]3.33 ± 1.32 3.74 ± 0.50 4.24 ± 1.71 0.246 neointimal area [mm²] 3.83 ±1.38 3.00 ± 0.55 2.72 ± 1.56 0.087 area stenosis [%] 53% ± 17% 44% ± 7% 39% ± 22% 0.106 injury score [—] 1.23 ± 0.91 1.14 ± 0.66 1.19 ± 0.230.963 inflammation score 1.48 ± 1.06 1.57 ± 0.63 0.71 ± 0.81 0.157 [—]

TABLE XIII Results of Histomorphometry for LAD only only LAD P DES DEB pn 28 7 7 vessel diameter [mm] 3.12 ± 0.14 3.03 ± 0.07 3.13 ± 0.14 0.258lumen diameter [mm] 1.93 ± 0.41 2.13 ± 0.48 2.17 ± 0.22 0.110 max.neoint. thickn. 0.73 ± 0.39 0.43 ± 0.29 0.64 ± 0.57 0.221 [mm] vesselarea [mm²] 7.73 ± 0.62 7.36 ± 0.32 7.38 ± 1.06 0.285 luminal area [mm²]2.91 ± 1.17 3.72 ± 1.35 4.52 ± 1.06 0.007 neointimal area [mm²] 4.82 ±1.37 3.65 ± 1.46 2.86 ± 1.41 0.004 area stenosis [%] 62% ± 15% 49% ± 18%38% ± 18% 0.002 injury score [—] 1.16 ± 0.83 1.36 ± 1.17 1.14 ± 0.590.856 inflammation score 1.43 ± 0.31 1.73 ± 1.16 0.79 ± 0.98 0.139 [—]

Tables XIV and XV summarize the individual results of histomorphometry.

TABLE XIV Individual Results of Histomorphometry for animalsG59/007-G59/028 ID group vesdia lumdia max thick vesarea lumarea neointarea stenosis injury inflammation G59007cx P 3.10 2.33 0.40 7.70 4.293.41 44.3% 0.50 0.44 G59007lad P 3.17 1.39 1.09 7.89 1.53 6.36 80.6%0.20 0.22 G59008cx P 3.02 1.93 0.66 7.19 2.89 4.30 59.9% 0.90 0.22G59008lad DEB 3.32 1.91 0.63 8.56 4.75 3.81 44.5% 0.86 1.33 G59009cx DEB3.04 2.32 0.48 7.26 3.28 3.98 54.8% 0.90 0.44 G59009lad P 3.32 2.40 0.388.59 4.55 4.04 47.1% 0.20 0.44 G59010cx P G59010lad P G59011cx DEB 2.981.15 0.93 6.92 1.33 5.59 80.8% 1.29 1.00 G59011lad P 3.09 2.14 0.38 6.993.34 3.65 52.3% 0.10 0.56 G59012cx P 3.21 2.02 0.66 7.92 3.24 4.68 59.1%1.00 0.44 G59012lad P 3.19 1.48 0.96 7.93 1.84 6.10 76.8% 2.00 2.33G59013cx DEB 3.11 2.52 0.14 7.57 5.57 2.00 26.4% 1.11 0.22 G59013lad P3.14 1.94 0.68 7.59 2.97 4.63 60.9% 1.30 1.56 G59014cx P 3.12 0.01 1.507.44 0.01 7.43 99.9% 3.00 3.00 G59014lad P 3.41 1.33 1.61 9.65 1.31 8.3586.5% 3.00 3.00 G59015cx P 3.07 1.89 0.73 7.59 2.84 4.74 62.5% 1.30 1.00G59015lad P 3.16 0.75 1.99 8.07 0.44 7.64 94.6% 1.80 2.44 G59016cx P3.28 2.45 0.30 8.30 4.74 3.56 42.9% 0.10 0.22 G59016lad DEB 3.25 2.280.35 8.13 4.41 3.72 45.8% 0.40 0.44 G59017cx P 2.78 1.16 0.88 5.96 1.041.92 82.6% 1.90 1.56 G59017lad P 3.15 1.74 0.71 7.75 2.47 5.28 68.1%0.80 0.78 G59018cx P 2.86 2.12 0.31 6.10 3.37 2.73 44.8% 0.40 0.44G59018lad P 2.78 1.84 0.71 7.45 2.71 4.74 63.6% 1.20 1.11 G59019cx DEB2.66 2.21 0.17 4.51 3.46 1.06 23.4% 1.00 0.22 G59019lad P 3.22 1.94 0.778.01 2.94 5.07 63.3% 0.70 0.89 G59020cx DEB 3.01 2.28 0.27 6.87 4.152.72 39.5% 1.11 0.22 G59020lad P 3.19 2.03 0.65 8.27 3.36 4.91 59.4%0.60 0.78 G59021cx P 2.85 1.96 0.47 6.33 3.10 3.23 51.7% 0.80 0.44G59021lad P 3.01 1.79 0.61 7.19 2.72 4.47 62.2% 0.60 0.67 G59022cx P2.61 1.64 0.48 5.30 2.29 3.01 56.9% 1.10 0.78 G59022lad P 3.01 2.13 0.467.02 3.43 3.59 51.2% 0.50 0.78 G59023cx P 3.11 1.78 0.67 7.48 2.54 4.9566.1% 1.00 1.00 G59023lad DEB 3.09 2.07 0.49 7.65 3.43 4.22 55.2% 1.100.44 G59024cx P 2.97 2.43 0.15 6.45 4.35 2.10 32.6% 0.10 0.11 G59024ladP 3.22 2.67 0.13 8.05 5.71 2.34 29.0% 0.40 0.00 G59025cx P 3.14 1.651.12 7.97 2.21 5.76 72.3% 1.50 1.22 G59025lad DEB 3.15 2.20 0.53 7.775.39 2.38 30.6% 0.50 0.22 G59026cx P 3.12 2.41 0.24 7.63 4.79 2.84 37.2%0.00 0.00 G59026lad DEB 3.07 2.52 0.16 7.62 5.68 1.93 25.4% 1.00 0.00G59027cx DEB 3.14 2.60 0.13 7.71 5.92 1.79 23.2% 0.75 0.33 G59027lad P3.27 2.10 0.55 8.28 3.65 4.62 55.9% 0.80 0.89 G59028cx P 2.75 1.84 0.365.79 2.77 3.01 52.1% 1.60 1.44 G59028lad DES 2.98 2.40 0.24 7.10 4.482.63 37.0% 0.20 0.22

TABLE XV Individual Results of Histomorphometry for animalsG59/029-G59/050 ID group vesdia lumdia max thick vesarea lumarea neointarea stenosis injury inflammation G59029cx DES 2.93 2.01 0.41 6.78 3.293.49 51.4% 0.70 0.89 G59029lad P 2.93 1.71 0.71 6.67 2.27 4.40 66.0%1.70 1.11 G59030cx DEB 3.19 2.51 0.22 7.87 5.95 1.92 24.4% 0.80 2.44G59030lad P 3.12 1.60 0.90 7.68 2.17 5.51 71.8% 0.90 1.00 G59031cx DES3.03 2.46 0.19 7.28 4.66 2.62 36.0% 0.60 2.22 G59031lad P 3.14 1.52 0.987.46 2.00 5.46 73.2% 2.70 2.78 G59032cx P 2.69 1.72 0.58 5.99 2.34 3.6560.9% 2.80 2.56 G59032lad P 3.10 2.40 0.44 7.73 4.52 3.22 41.6% 0.202.67 G59033cx P 3.19 1.79 0.92 8.41 2.65 5.76 68.5% 3.00 3.00 G59033ladDES 3.10 1.16 1.02 7.84 1.11 6.73 85.9% 3.00 3.00 G59034cx P 2.83 2.190.25 6.19 3.67 2.53 40.8% 0.40 2.78 G59034lad DES 3.04 2.37 0.24 7.304.36 2.95 40.3% 1.20 2.56 G59035cx P 3.09 2.58 0.25 7.61 5.73 1.89 27.8%1.20 1.78 G59035lad DES 3.07 2.37 0.38 7.54 4.33 3.20 42.5% 1.00 1.67G59036cx P 3.16 2.39 0.48 7.95 4.65 3.30 41.5% 1.00 1.44 G59036lad P3.01 2.38 0.38 7.19 4.39 2.80 39.0% 0.50 1.22 G59037cx P 3.17 2.73 0.237.76 5.59 2.17 28.0% 0.10 1.00 G59037lad P 3.08 2.32 0.35 7.54 4.26 3.2843.5% 0.70 1.11 G59038cx P G59038lad DEB G59039cx DES 2.89 2.05 0.486.55 3.26 3.28 50.2% 1.90 1.00 G59039lad P 3.13 2.10 0.61 7.80 3.43 4.3656.0% 1.30 2.00 G59040cx P 3.03 2.18 0.32 7.25 3.74 3.51 48.4% 1.70 1.22G59040lad DES 3.12 2.61 0.17 7.66 5.23 2.43 31.7% 0.50 0.33 G59041cx DES2.84 2.26 0.22 6.49 4.05 2.45 37.7% 0.70 1.22 G59041lad P 3.27 2.05 0.618.38 3.59 4.79 57.1% 1.70 2.33 G59042cx P 2.84 2.29 0.25 6.23 3.96 2.2736.4% 0.90 4.00 G59042lad DEB 3.14 2.29 1.88 5.47 5.18 0.29 5.2% 0.800.33 G59043cx DES 2.42 2.16 0.27 6.02 3.74 2.28 37.9% 1.20 1.44G59043lad P 3.00 2.03 0.41 7.12 3.48 3.65 51.2% 1.00 1.78 G59044cx P3.04 1.65 0.80 7.68 2.12 5.55 72.3% 3.00 3.00 G59044lad DES 2.96 2.000.44 7.02 3.31 3.71 52.9% 3.00 3.00 G59045cx DES 2.96 2.24 0.35 6.973.82 3.15 45.2% 1.80 1.56 G59045lad P 3.01 1.97 0.55 7.34 3.12 4.2257.5% 1.50 1.56 G59046cx DES 2.91 1.98 0.44 7.09 3.36 3.73 52.6% 1.902.44 G59046lad P 2.96 1.50 1.00 7.09 1.83 5.27 74.2% 1.90 1.44 G59047cxP 2.98 2.21 0.36 7.21 3.78 3.43 47.5% 2.00 1.78 G59047lad P 2.98 1.560.79 7.20 1.90 5.30 73.6% 1.80 1.22 G59048cx P 3.10 2.63 0.14 7.61 5.152.46 32.3% 0.60 1.00 G59048lad DES 2.96 2.01 0.50 7.08 3.21 3.87 54.7%0.80 1.22 G59049cx P 3.15 1.75 0.83 7.99 2.45 5.54 69.3% 1.60 2.00G59049lad DEB 2.87 1.90 0.44 6.46 2.80 3.66 56.7% 2.30 2.78 G59050cx P3.11 1.99 0.58 7.46 2.94 4.51 60.5% 1.70 2.22 G59050lad P 3.35 1.41 1.128.45 1.63 6.82 80.7% 2.90 2.44

4. Conclusion:

The studies indicate show a significant reduction of neointimalformation by the Zotarolimus coated stent and coated balloon. Theefficacy in reduction of neotintimal formation by the Zotarolimus coatedballoon is comparable to the Zotarolimus coated stent, and in someinstances the zotarolimus coated balloon has greater efficacy than thezotarolimus coated stent.

The methods and systems of the present invention, as described above andshown in the drawings, provide for a balloon catheter with superiorproperties including superior therapeutic agent delivery andpost-deployment catheter withdrawal capabilities. It will be apparent tothose skilled in the art that various modifications and variations canbe made in the device and method of the present invention withoutdeparting from the spirit or scope of the invention. For example, theinstant invention can work particularly well to treat dialysis grafts.As is well known in the art, dialysis grafts are essentially sheathsconnecting the arterial and venous sides of a patient's vasculature asis required when a patient is on dialysis for kidney failure. As thesesheaths have a tendency for rapid and substantial restenosis, theabove-described embodiments would be advantageous as an anti-restenoicagent could be delivered to the graft and the delivery would be lesstraumatic and more easily adjusted to fit the anatomy of the grafts.Thus, it is intended that the present invention include modificationsand variations that are within the scope of the appended claims andtheir equivalents.

1. A balloon catheter comprising: an inner shaft member having aproximal end portion, a distal end portion, and a length therebetween;an outer shaft member movable relative to the inner shaft member havinga proximal end portion, a distal end portion, and a length therebetween;an annular flow passage disposed between the inner and outer shaftmembers; a flexible membrane extending between the distal end portion ofthe inner shaft member and the distal end portion of the outer shaftmember; wherein the flexible membrane includes an inner surface and anouter surface, the inner surface configured in fluid communication withthe annular flow passage; and wherein the flexible membrane includes atherapeutic agent disposed thereon.
 2. The balloon catheter of claim 1wherein the outer shaft member is axially movable relative to the innershaft member.
 3. The balloon catheter of claim 2 including a bellowscomponent disposed at the proximal end portion of the outer shaft memberto maintain a sealed environment of the annular flow passage duringmovement of the outer shaft relative to the inner shaft.
 4. The ballooncatheter of claim 2 including a dynamic seal disposed between the innershaft member and the outer shaft member to maintain a sealed environmentof the annular flow passage during movement of the outer shaft relativeto the inner shaft.
 5. The balloon catheter of claim 1 wherein the outershaft member and the inner shaft member define a chamber configured toreceive the flexible membrane therein.
 6. The balloon catheter of claim5 wherein the outer surface of the flexible membrane is attached to theinner surface of the outer shaft member and the outer surface of theflexible membrane is attached to the outer surface of the inner shaftmember.
 7. The balloon catheter of claim 1 wherein the outer shaftmember is rotatably movable relative to the inner shaft member.
 8. Theballoon catheter of claim 7 including a dynamic seal disposed betweenthe inner shaft member and the outer shaft member to maintain a sealedenvironment of the annular flow passage during movement of the outershaft relative to the inner shaft.
 9. The balloon catheter of claim 7wherein, in a pre-deployed condition, the flexible membrane includesspiral formations.
 10. The balloon catheter of claim 1 including aretrieval element attached to the inner shaft member.
 11. A ballooncatheter comprising: an inner shaft member having a proximal endportion, a distal end portion, and a length therebetween; an outer shaftmember movable relative to the inner shaft member having a proximal endportion, a distal end portion, and a length therebetween; an annularflow passage disposed between the inner and outer shaft members; aflexible membrane extending between the distal end portion of the innershaft member and the distal end portion of the outer shaft member;wherein the flexible membrane includes an inner surface and an outersurface, the inner surface configured in fluid communication with theannular flow passage; and wherein the flexible membrane includes atleast one driver segment and a delivery segment, wherein the driversegment defines at least a portion of a chamber configured to receivethe delivery segment; and wherein the driver segment is constructed of amaterial having different compliance than that of the delivery segment.12. The balloon catheter of claim 11 wherein the flexible membraneincludes a proximal driver segment, a distal driver segment, and adelivery segment therebetween.
 13. The balloon catheter of claim 12wherein the proximal driver segment and the distal driver segment enfoldthe delivery segment to define the chamber configured to receive thedelivery segment.
 14. A method of treating a luminal system of a patientcomprising: providing a balloon catheter including: an inner shaftmember having a proximal end portion, a distal end portion, and a lengththerebetween; an outer shaft member movable relative to the inner shaftmember having a proximal end portion, a distal end portion, and a lengththerebetween, with an annular flow passage disposed between the innerand outer shaft members; a flexible membrane extending between thedistal end portion of the inner shaft member and the distal end portionof the outer shaft member, the flexible membrane having an inner surfaceand an outer surface with the inner surface in fluid communication withthe annular flow passage; and a therapeutic agent disposed on theflexible membrane; positioning the balloon catheter at a desireddeployment site; moving the outer shaft member relative to the innershaft member; and introducing inflation fluid into the annular flowpassage, simultaneously or sequentially with said relative movement, todeploy the flexible membrane into an expanded configuration to treat theluminal system of a patient.
 15. The method of claim 14 wherein initialdeployment of the flexible membrane at least partially occludes theluminal system of the patient prior to full expansion of the flexiblemembrane.
 16. The method of claim 14 wherein the flexible membrane, in apre-deployment state, includes spiral formations and deployment isaccomplished by rotational movement of the outer shaft member relativeto the inner shaft member.
 17. The method of claim 14 wherein theflexible membrane is collapsed after deployment and treatment of theluminal system of the patient.
 18. The method of claim 17 wherein theflexible membrane is collapsed by withdrawing inflation fluid from theannular flow passage
 19. The method of claim 17 wherein the flexiblemembrane is collapsed by movement of the outer shaft member axiallyrelative to the inner shaft member.
 20. The method of claim 17 whereinthe flexible membrane is repositioned upon collapse into a chamberconfigured to receive the flexible membrane, wherein the chamber isdefined by the outer shaft member and the inner shaft member.